A major challenge in neurobiology is the identification of the mechanisms by which protein misfolding leads to cellular toxicity. Many neurodegenerative disorders, in which aberrant protein conformers aggregate into pathological inclusions, present the chronic activation of the PERK branch of the unfolded protein response. The adaptive effects of the PERK pathway include reduction of translation by transient inhibition of eIF2α and antioxidant protein production via induction of Nrf2 transcription factor. In contrast, PERK prolonged activation leads to sustained reduction in protein synthesis and induction of cell death pathways. To further investigate the role of the PERK pathway in neurodegenerative disorders, we focused on Down syndrome (DS), in which aging confers a high risk of Alzheimer disease (AD). By investigating human DS frontal cortices, we found early and sustained PERK activation associated with the induction of eIF2α and ATF4 downstream signals. We also observed that the Nrf2 response is uncoupled from PERK and its antioxidant effects are repressed in a mechanism implicating the transcription repressor Bach1. The pharmacological inhibition of PERK in DS mice reduced eIF2α-related translational repression and promoted Nrf2 nuclear translocation, favoring the rescue of Nrf2/Bach1 imbalance. The further analysis of peripheral cells from living DS individuals provided strong support of the pathological link between PERK and trisomy 21. Our results suggest that failure to regulate the PERK pathway is a peculiar characteristic of DS pathology and it may represent an essential step to promote cellular dysfunction, which actively contributes in the brain to the early development of AD.
|Journal||Progress in Neurobiology|
|State||Published - Jan 2021|
Bibliographical noteFunding Information:
This work was funded by Sapienza University of Rome - Progetti d'AteneoRG1181642744DF59, RM11715C773949E3 and RG116154C9214D1A, by Istituto Pasteur Italia – Fondazione Cenci Bolognetti Under 45 U-4.IT, and by Ministry of HealthGR-2018-12366381to F.D.D.; J.F.A support pertinent to this work came from Alzheimer's AssociationNIRG-14-322441, Department of DefenseAZ140097, NIH/NIMHD L32 MD009205-01, NIH/NINDS 1R01 NS091329-01. D.A.B and E.H were supported in part by NIHAG055596.
This work was funded by Sapienza University of Rome - Progetti d’Ateneo RG1181642744DF59 , RM11715C773949E3 and RG116154C9214D1A , by Istituto Pasteur Italia – Fondazione Cenci Bolognetti Under 45 U-4.IT, and by Ministry of Health GR-2018-12366381 to F.D.D.; J.F.A support pertinent to this work came from Alzheimer’s Association NIRG-14-322441 , Department of Defense AZ140097 , NIH/NIMHD L32 MD009205-01 , NIH/NINDS 1R01 NS091329-01 . D.A.B and E.H were supported in part by NIHAG055596.
© 2020 Elsevier Ltd
- Down syndrome
- Protein translation
- Unfolded protein response
ASJC Scopus subject areas
- Neuroscience (all)